5-(5-nitro-2-furyl-mono- and di-vinylene)-1, 3, 4-oxadiazoline-2-one and process



United States Patent 3,146,232 S-(S-NITRO-Z-FURYlL-MONO- AND DI-VINYLENE)- 1,3,4-XADIAZOLINE-2-0NE AND PROCESS Haruo Saiiraehi, 432 Ryutozaki oaza Kanehira, Fukuoka,

Japan; Akin ()yama, 55 Shimogamo-shibamoto-cho, Sakyo-ku, Kyoto, Japan; Ryuzo Ueno, 65 Nango-cho, Nishinomiya, Japan; and Hiroshige Inoue, 2-136 Nishimikuni-cho, Higashiyodogawa-hu, Osaka, Japan No Drawing. Filed Sept. 17, 1962, Ser. No. 224,200 3 Claims. (Cl. 260240) This invention relates to a series of novel compounds having the formula:

N NH

wherein n is an integer from 1 to 2. (In the following, the compound of n=1 will be described as Compound I and that of n=2 as Compound II.)

The new compounds specified above are crystalline solids somewhat soluble in an organic solvent such as methanol, ethanol, acetone and dioxane and of low watersolubility. They have been found to be very active as inhibitory agents against the growth of microorganisms.

5 (S-nitro-2-furyl)-1,3,4-oxadiazoline-2-one disclosed in the United States Patent 2,918,473 is a similar compound. But the present invention is based upon the discovery that a vinyl group binding the 1,3,4-oxadiazoline- 2-one groups which are bonded to the nitrofuran nucleus at position 2 plays a very pronounced part in increasing antimicrobial efficacy, in lowering toxicity on animals and in maintaining in vivo activity.

The properties of the compounds of this invention are as follows:

Cultivated at 37 C. [or 48 hours. The culture base used Iconsists of 0.5% of peptone, 0.5% of glucose and 0.3% of extracted yeast, and is adjusted to pH 7.0 and sterilized under 1.46 kglcm. steam pressure for 20 it r l rhinistered orally to rabbits in amount of 100 mgJkg. and measured after 4 hours.

The compounds of this invention exhibit a pronounced activity in effectively combating Eimeria tenella and Trichomonas vaginalis organisms when administered orally. But the compounds show no toxicity on the animals. This fact is presumably due to a slight difference between the in vitro and the in vivo activity. For instance, Cornpound I produces a complete cure on domestic fowls infected with coccidium when incorporated in their feed at the level of 0.01% by Weight. The LD in mice of Compound I and Compound II is respectively 300 mg./ kg. and 1.0 g./kg., and Compound I produces no chronic toxicity on rats when administered in amount of 30 mg./ kg. for 6 months.

In view of these findings, the compounds of this invention can be employed as very effective antiseptic and antimicrobial agents and parasiticides without any danger of adverse effect.

The loss of in vivo activity, furthermore, being very slight, the compounds of this invention can be effectively employed with other agents which are apt to lose in vivo activity. The dosage can accordingly be confined to a minimum amount, and the compounds can be profitably employed by mixing in foodand feedstufis. As preservatives, Compounds I and I produce a satisfactory antiseptic effect within the range of 10 to 2-0 p.p.m.

The compounds of this invention may be administered with an inert powder as a dust or as a tablet. They may also be dispersed in water with an appropriate dispersant or emulsifying agent, or dissolved in an organic solvent such as propylene glycol. The dispersion or solution thus prepared is sprayed or coated onto a harvested or finished article, or the article to be protected is dipped in said dispersion or solution. Said compounds can further be mixed in foodand feedstuff materials.

The method of preparing the compounds of this invention comprises reacting hydrazine hydrate with 5-nitro-2- furyl monoor divinylene carboxylic acid chloride having -CH CH- or CH=CHCH=CH- group, and then treating the resultant acid hydrazide with phosgene.

In carrying out the reaction, S-nitro-Z-furyl monoor divinylene carboxylic acid chloride having the formula:

wherein n is an integer from 1 to 2, is dissolved in an organic solvent, and the resultant solution is mixed dropwise in a cooled aqueous solution of hydrazine hydrate. The precipitating crystalline product 5-nitro-2-furyl acrylic acid hydrazide or 5-nitro-2-furyl divinylene carboxylic acid hydrazide is separated by filtration, dissolved in an aqueous solution of hydrogen chloride, and then phosgene gas is introduced beneath the surface of the resultant solution at a temperature ranging from 0 to C. Upon completion of the reaction, the precipitating yellow crystalline product is separated by filtration and recrystallized according to the ordinary method.

Preferred examples are as follows, but they are not construed as limiting the scope and extent of the invention:

EXAMPLE 1 5-(5-Nitro-2-Furylvinylene)-J,3,4-Oxadiaz0line-2-One O N NH and iion=oni=0 A solution of 201.5 g. of 5-nitro-2-furylacrylic acid chloride in 1,000 cc. of benzene is cooled and added dropwise with stirring to an aqueous solution of 313 g. of 80% hydrazine hydrate in 2 liters of water during 2 hours. Stirring is further continued for 30 minutes. The resulting precipitate is separated by filtration and dissolved with stirring in an aqueous solution of 500 cc. of concentrated hydrochloric acid in 2,500 cc. of water at room temperature. The resultant solution is cooled to 10 C. and phosgene gas is introduced portionwise beneath the surface of the liquid reaction mixture with stirring during 2 hours at a temperature not higher than 80 C. The crystalline product which forms during the reaction is separated by filtration. Upon recrystallization from an acetone-water mixture, there are obtained 126 g. of 5-(5-nitro-2-furylvinylene)-1,3,4-oxadiazoline-2-one as yellow crystalline solids which melt at 213 C. with decomposition. Yield is 55%.

Analysis.Calcd. for C H N O C=43.05%; H=2.26%; N=18.83%. Found: C=43.35%; H=2.01%; N=18.80%

EXAL EPLE 2 5- (5-Nitr0-2-Furyldivinylene)-1,3,4-0xadiaz0Iine-2-One GHQH NNH GEN- -CH=CHCH=CH- A solution of 45.5 g. of -nitro-2-furylpentadienic acid chloride in 500 cc. of benzene is cooled and added drop- Wise with stirring to an aqueous solution of 200 g. of 80% hydrazine hydrate in 1,600 cc. of water during 1 hour. Stirring is continued for 30 minutes. The precipitate which forms is separated by filtration and dissolved with stirring in an aqueous solution of 250 cc. of concentrated hydrochloric acid in 2,500 cc. of water at room temperature. The resultant solution is cooled to C. and phosgene gas is introduced portionwise beneath the surface of the liquid reaction mixture during 2 hours at a temperature not higher than 80 C. The crystalline precipitate which forms during the reaction is separated by filtration. Upon recrystallization from a dioxane-water mixture, there are obtained 17.4 g. of a yellow crystalline product which melts at a temperature above 250 C. with decomposition. Yield is 35%.

Analysis.Calcd. for C H N 0 C=48.20%; H=2.83%; N=17.27%. Found: C=48.46%;

4 What is claimed is: 1. A compound of the formula:

|3HCH O2N-C wherein n is an integer selected from the group consisting of 1 and 2.

2. 5-(5-nitro-2-furylvinylene) 1,3,4 oxadiazoline-Z- one.

3. 5-(S-nitro-2-furyldivinylene) 1,3,4 oxadiazoline- 2-or1e.

References Cited in the file of this patent German Patentanmeldung F 12,656 IVb/lZp, April 19, 1956.

Darnow et al.: Chem. Ber., vol. 82, pages 121 to 123 (1949).

Chemical Abstracts, vol. 54, cols. 17359 to 17360 (1960), QDl A51. (Abstract of Saikachi et al., Chem. Pharm. Bull. (Tokyo), vol. 7, pages 584-8 (1959).)

Chemical Abstracts, vol. 55, col. 7380 (1961), Q1) 1A51. (Abstracts of Saikachi et al., Yakugaku Zasshi, vol. 80, pages 1584-8 (1960).) 

1. A COMPOUND OF THE FORUMLA: 